Trial Drugs for Huntington's Disease Inconclusive in Slowing Disease

A large-scale clinical trial that tested the ability of the investigational drugs remacemide and Coenzyme Q10 to slow the progression of Huntington's disease showed that neither drug resulted in any significant improvement for the patients. Although after one year of treatment, the disease seemed to progress more slowly in patients treated with Coenzyme Q10, the investigators say that overall the results are inconclusive as to whether there is real benefit from this drug. The study is published in the August 14, 2001, issue of Neurology. *

"The Coenzyme Q10 and Remacemide Evaluation in Huntington's Disease," or CARE-HD trial, was conducted for 30 months by the Huntington Study Group at 23 sites in the United States and Canada. The trial included 347 people in the early stages of the disease. It was funded by the National Institute of Neurological Disorders and Stroke (NINDS), and is the largest study to investigate treatments for Huntington's disease.

Remacemide is a new investigational drug that blocks a neurotransmitter in the brain (the NMDA glutamate receptor) which has long been suspected of contributing to the death of brain cells in Huntington's disease. Coenzyme Q10 is a substance that occurs naturally in the body and plays a role in the function of mitochondria, the energy factories of human cells. It is also an anti-oxidant, meaning that it can neutralize potentially injurious oxygen-containing chemicals called free radicals, which may play a role in the nerve cell death that occurs in Huntington's disease. Coenzyme Q10 is sold as a nutritional supplement in pharmacies and health food stores.

Participants in the randomized, double-blind CARE-HD study were assigned to one of four treatments: 25% received remacemide, 25% received Coenzyme Q10, 25% received the combination of Coenzyme Q10 and remacemide, and 25% received placebo (no active medication). Each participant was followed with standardized tests for neurological and neuropsychological function.

To determine the effectiveness of the study drugs, investigators looked for a reduction in the patients' functional decline as measured by the Total Functional Capacity scale (TFC). A score of 13 represents a normal degree of function and a score of 0 represents a severely disabled state. CARE-HD participants had a mean TFC score of approximately 10.

The investigators reported the following results:

The condition of patients in the placebo group worsened by 2.7 units on the TFC scale over the 30 months of the trial.

The condition of patients who were treated with remacemide also worsened by 2.7 points on the TFC scale over the course of the study, showing that the drug had no appreciable effect on functional decline. In the remacemide-treated group, however, there was a trend toward improvement in the degree of the patients' chorea. Although this effect was not considered statistically significant, it was seen during the patients' first visit after treatment began, suggesting that the drug may decrease chorea. Remacemide was well tolerated overall, although there was an increase in some side effects, primarily lightheadedness, dizziness, and nausea.

Patients who were treated with Coenzyme Q10 also failed to show a statistically significant decrease in TFC decline over the duration of the 30-month trial. However, after the first year, the condition of the study participants treated with Coenzyme Q10 worsened at a slower rate, with approximately 13% less decline on the TFC scale compared to those not receiving Coenzyme Q10. A similar trend toward a decrease in functional decline was seen in two other scales that measure functional capacity. In addition, on two cognitive scales there was a slower decline in the group receiving Coenzyme Q10. On no measure was Coenzyme Q10 associated with a worsening of the disease, and there were no apparent side effects, with the exception of gastrointestinal upset.

The CARE-HD investigators, the Huntington's Disease Society of America, the Huntington's Disease Society of Canada, and the Hereditary Disease Foundation, who jointly cooperated on the study, all agree that the data are inconclusive about whether there is clear benefit of Coenzyme Q10 on functional decline. The statistical analysis of the CARE-HD data indicates that the apparent benefit attributed to Coenzyme Q10 could have occurred by chance. The investigators and the cooperating groups urge patients with Huntington's disease to discuss the pros and cons of changing their therapy with their physicians.

"Despite the fact that the results of this trial are inconclusive, the study does provide the hope that an agent many someday be found which will slow the progression of Huntington's disease and other neurodegenerative disorders, " said Eugene J. Oliver, Ph.D., program director at the NINDS.

Because Coenzyme Q10 is an unregulated dietary supplement, formulations may differ. The authors point out that there were no adverse effects (outside of gastrointestinal upset) with Coenzyme Q10, but given the lack of definite evidence that any benefit will result, the cost of taking the drug over years may be significant. In addition, the results of the CARE-HD study cannot be applied to persons at risk for Huntington's disease or those whose are in later disease stages.

"CARE-HD is important because it is the first study to show a hopeful trend toward slowing of disease with a particular therapy and gives us some good clues to work with in future studies," said Walter J. Koroshetz, M.D., of Massachusetts General Hospital in Boston, and a co-principal investigator of the study. "We hope that further research will build on the CARE-HD trial and lead to an effective treatment that significantly slows progression of Huntington's disease and eventually to a cure for these patients," said Dr. Koroshetz. "The real heroes of this study were the participants with HD and their families," he added.

Huntington's disease is an inherited disorder affecting 30,000 Americans. It is caused by a single genetic mutation identified in 1993. People who inherit the defective gene from one of their parents develop degeneration of specific brain regions. Symptoms usually begin in early to mid-adulthood, but children are occasionally affected. Signs of the illness include involuntary movements called chorea, as well as motor and cognitive difficulties. It is a progressive disease that leads to death 15-20 years after diagnosis.

Additional support for this study was provided by Astra Zeneca, the makers of remacemide, and by Vitaline Corporation, which supplied the Coenzyme Q10.

NINDS is a component of the National Institutes of Health in Bethesda, Maryland, and is the nation's primary supporter of biomedical research on the brain and nervous system. The Institute is celebrating its 50th anniversary this year.